Polycystic ovary syndrome (PCOS) is the most common cause of female infertility and results in a substantial financial burden to the American healthcare system. PCOS patients experience gynecological symptoms, such as infertility and recurrent pregnancy loss, and also a metabolic syndrome of obesity and hyperinsulinemic insulin resistance. Despite the importance of this disorder, the definitive etiology of PCOS is not known. Under the direction Dr. Krisher, Dr. Newell-Fugate validated the obese Ossabaw pig as an animal model of PCOS which embodies the reproductive characteristics of the disease and which is accessible for large scale research. The obese Ossabaw pig meets all of the Rotterdam PCOS diagnostic criteria- hyperandrogenemia, cystic ovaries, and elongated estrous cycles (oligoovulation)-in addition to having hyperinsulinemia and hyperglycemia. The objective of this K01 grant, which will foster Dr. Newell-Fugate's development as an independent investigator, is to examine the steroidogenic aberrations which lead to hyperandrogenemia and the interrelationship between hyperandrogenemia and the endometrium in the obese Ossabaw pig model of PCOS. Based on our preliminary data, we hypothesize that the obese Ossabaw pig will mimic PCOS steroidogenic aberrations and provide clues to implantation failure due to endometrial dysfunction in human PCOS patients. Using our PCOS model animal, we plan to accomplish our objective through pursuit of two specific aims: 1) Examine the ovary and adrenal to elucidate the steroidogenic mechanisms responsible for the elevated androgen concentrations;2) Assess gene regulation and protein expression in the secretory endometrium during the implantation window. Similar to PCOS in humans, we expect that our model animal to have a pathogenic biochemical and molecular basis for abnormal androgen production and altered progesterone regulated gene expression in the endometrial implantation window. The mentors on this application are well-prepared to guide Dr. Newell-Fugate in the project due to their extensive research backgrounds in endocrinology, uterine biology, and human PCOS. The proposed research is innovative because it will develop a model animal for PCOS to facilitate development and testing of treatment modalities for infertility due to ovarian and endometrial dysfunction. Lastly, the research proposed and career development and training activities outlined, will prepare Dr. Newell-Fugate for the independent investigator stage of her scientific career. PUBLIC HEALTH RELEVANCE (provided by applicant): Polycystic ovary syndrome (PCOS) manifests reproductive (infertility), endocrine (androgen excess), and metabolic (obesity and insulin resistance) pathologies and is the most prevalent reproductive endocrine disorder in women, resulting in a significant burden to the American healthcare system. With the continued characterization of our Ossabaw pig model, we will elucidate the similarities in steroidogenic pathophysiology between our model animal and human PCOS and will determine the specific effects of hyperandrogenemia on the implantation endometrial environment. Further characterization of such a model animal will establish its utility in the development and testing of new clinical treatments for the reproductive and endocrine symptoms of PCOS.